Patient-specific Outcomes Research Articles

Development and validation of a prognostic model for advanced gastric and oesophageal carcinoma (AGOC) using individual patient data from two clinical trials.

499 Background: Estimating survival in advanced gastric and oesophageal carcinoma (AGOC) remains a significant challenge. We developed a prognostic model incorporating readily accessible patient and clinical data and specific patient-reported outcomes (PROs), utilizing individual participant data from two randomized trials. Methods: We used data from 2 trials comparing regorafenib to placebo; AGITG INTEGRATE IIa (n=251) for model development and AGITG INTEGRATE (n=152) for validation. Both trials enrolled metastatic or AGOC following failure of 1 or more prior lines of systemic therapy. Candidate variables were chosen from systematic literature review and expert consultation. Significant prognostic factors for inclusion in the multivariable model were identified using univariable Cox proportional hazards models with p-value threshold of 0.1. Multivariable models were developed via Lasso regression. An initial model was created using clinical variables alone, followed by the integration of PROs. C statistics were used to discriminate the model’s efficiency. Results: Univariable analysis identified 9 clinical variables and 4 PRO domains as significant, including body mass index (BMI)(p=0.08), ECOG PS (0.02), extent of cancer (p<0.001), liver involvement (p=0.04), treatment with regorafenib (p=0.005), neutrophil-lymphocyte ratio (NLR) (p<0.001), LDH (p<0.001), albumin (p<0.001), and CA 19-9 (p=0.007). Significant baseline PROs included appetite loss (p<0.001), constipation (p<0.001), fatigue (p<0.001), and pain (p<0.001). Gastrectomy violated the Cox model proportional hazards assumption necessitating that the analysis be stratification by gastrectomy. The primary model (M1) incorporated region (Asia vs non-Asia, p=0.25, was included because it was significant in previous analysis (INTEGRATE), ECOG PS status, cancer extent, treatment with regorafenib, NLR, BMI, LDH, CA 19-9, and albumin. The final model (M2), which included PROs, demonstrated superior discriminative ability with the highest c-statistic values in both the gastrectomy and non-gastrectomy strata. The c-statistic increased from 0.695 for M1 to 0.723 for M2, indicating the added prognostic value of including PROs. Conclusions: The prognostic model that integrated both clinical data and PROs, proved robust for predicting survival in AGOC. The addition of PROs significantly enhanced prognostic accuracy, highlighting their importance in survival models. Further validation and refinement of the model is ongoing.

Evaluation of Multispecific Drugs Based on Patient-Derived Immunocompetent Tumor Organoids.

The evolution of antitumor drug development has transitioned from single-agent chemotherapy to targeted therapy, immunotherapy, and more recently, multispecific drugs. These innovative drugs target multiple cellular or molecular pathways simultaneously, offering a more comprehensive anticancer approach and addressing some of the limitations inherent in traditional monotherapies. However, preclinical assessment of multispecific drugs remains challenging, as conventional tumor models often lack the necessary complexity to accurately reflect the interactions between various cell types and targets. Patient-derived immunocompetent tumor organoids (PDITOs), which incorporate both tumor cells and immune cells, present a promising platform for the evaluation of these drugs. Beyond their use in drug evaluation, PDITOs can also be utilized in personalized drug screening and predicting patient-specific treatment outcomes, thus advancing both multispecific drug development and precision medicine. This perspective discusses the current landscape of multispecific drug development and the methodologies for constructing PDITOs. It also addresses the associated challenges and introduces the concept of employing these organoids to optimize the evaluation and rational design of multispecific drug therapies.

Navigating the Complexities of Range of Motion in Reverse Shoulder Arthroplasty: Innovations and Future Directions.

With the growing popularity and broadening indications for Reverse Shoulder Arthroplasty (RSA), increasing modularity in design and adjustments to each component can enhance postoperative range of motion (ROM), thus expanding treatment capabilities. This review outlines the advancements developed to optimize ROM through modifications in glenoid and humeral components and the integration of computational tools for surgical planning. Enhancements in glenoid component design aim to mitigate complications like scapular notching and improve ROM, particularly in abduction and external rotation. Modifications to the humeral component, including adjustments in neck-shaft angle and lateralization, also contribute to ROM optimization. The integration of computational modeling and intraoperative navigation is advancing towards a more tailored approach to RSA to increase postoperative ROM. While RSA has evolved considerably since the introduction of the Grammont prosthesis, current research continues to improve upon implant design and positioning to overcome early design limitations. Modifications such as glenoid lateralization and inferior positioning and humeral neck-shaft angle and lateralization contribute to better postoperative ROM. The integration of these advancements in implant adjustments with computational modeling for surgical planning has the potential to enhance ROM and patient-specific outcomes. Translating these biomechanical improvements into clinical benefit remains a key area for future investigation.

Comparative Predictors of Long-Term Success in Mesh-Based versus Tissue-Only Hernia Repair: A Meta-Analysis

Introduction: Hernia repair ranks among the most commonly performed surgical procedures worldwide, with two predominant approaches: mesh-based and tissue-only techniques. Mesh repairs, while effective in reducing recurrence rates, are associated with complications like chronic pain and foreign body reactions. Conversely, tissue-only repairs avoid these complications but tend to have higher recurrence rates, particularly in complex hernias. This study aims to evaluate long-term predictors of success for both techniques to inform optimal surgical decision-making. Objective: To compare prognostic factors for mesh-based versus tissue-only hernia repair, emphasizing recurrence rates, complications, and patient-specific outcomes. Methods: A meta-analysis of randomized controlled trials and cohort studies published between 2000 and 2024 was conducted using PubMed, Scopus, Web of Science, and Cochrane databases. Studies with a minimum follow-up of one year were included. Data were analyzed using random effects models to evaluate recurrence, complications, and patient characteristics. Results: Mesh-based repairs demonstrated significantly lower recurrence rates, particularly in patients with large hernias or higher BMI. Lighter-weight meshes were associated with reduced chronic pain. Tissue-only repairs were more suitable for younger, slimmer patients with smaller hernias, demonstrating fewer complications but higher recurrence rates in complex cases. The findings underscore the importance of tailoring the surgical approach to patient-specific factors. Conclusion: The results highlight the need for individualized surgical strategies in hernia repair. Mesh-based techniques are recommended for complex cases due to their lower recurrence rates, while tissue-only repairs are more suitable for young, low-risk patients. These insights can guide clinicians in selecting the most appropriate repair technique, improving patient outcomes and satisfaction. By focusing on long-term predictors of success, this study provides a comprehensive evaluation of mesh-based and tissue-only hernia repairs, offering valuable guidance for patient-centered surgical decision-making.

Finite element analysis of a novel patellar fracture fixation method

BackgroundPatellar fractures present challenges in treatment, with traditional methods often leading to complications such as loss of reduction and implant failure. This study aimed to compare a novel suture fixation technique with the traditional tension band method using finite element analysis.MethodsCT images of a healthy 35-year-old male were used to construct 3D patellar models. Two fixation methods were modeled: the novel suture technique using polyester sutures and traditional tension band fixation with Kirschner wires and cerclage wires. Finite element analysis was conducted to compare stress and pressure distribution under varying force angles.ResultsThe novel suture fixation method demonstrated superior stress dispersion and more uniform pressure distribution compared to the traditional tension band technique. Stress concentration was notably reduced, indicating potential for enhanced fracture stability and healing. Tensile testing confirmed the mechanical properties of the sutures, further validating the proposed method.ConclusionsFinite element analysis revealed that the novel suture technique for patellar fractures provides better stress and pressure distribution compared to traditional methods. This approach offers promise for improved fracture stability and reduced complications. Clinical validation and long-term follow-up studies are warranted to confirm these findings and assess patient-specific outcomes.

Preclinical Models for Functional Precision Lung Cancer Research.

Patient-centered precision oncology strives to deliver individualized cancer care. In lung cancer, preclinical models and technological innovations have become critical in advancing this approach. Preclinical models enable deeper insights into tumor biology and enhance the selection of appropriate systemic therapies across chemotherapy, targeted therapies, immunotherapies, antibody-drug conjugates, and emerging investigational treatments. While traditional human lung cancer cell lines offer a basic framework for cancer research, they often lack the tumor heterogeneity and intricate tumor-stromal interactions necessary to accurately predict patient-specific clinical outcomes. Patient-derived xenografts (PDXs), however, retain the original tumor's histopathology and genetic features, providing a more reliable model for predicting responses to systemic therapeutics, especially molecularly targeted therapies. For studying immunotherapies and antibody-drug conjugates, humanized PDX mouse models, syngeneic mouse models, and genetically engineered mouse models (GEMMs) are increasingly utilized. Despite their value, these in vivo models are costly, labor-intensive, and time-consuming. Recently, patient-derived lung cancer organoids (LCOs) have emerged as a promising in vitro tool for functional precision oncology studies. These LCOs demonstrate high success rates in growth and maintenance, accurately represent the histology and genomics of the original tumors and exhibit strong correlations with clinical treatment responses. Further supported by advancements in imaging, spatial and single-cell transcriptomics, proteomics, and artificial intelligence, these preclinical models are reshaping the landscape of drug development and functional precision lung cancer research. This integrated approach holds the potential to deliver increasingly accurate, personalized treatment strategies, ultimately enhancing patient outcomes in lung cancer.

Biological and Synthetic Materials in Mandibular Reconstruction

Mandibular reconstruction is a critical surgical procedure necessary for restoring both function and aesthetics following trauma, tumor resection, or congenital defects. Over time, a variety of biological and synthetic materials have been developed to address the challenges of reconstructing the complex anatomy of the mandible. Biological materials, such as autografts, offer superior biocompatibility and osteogenic potential, but are limited by donor site morbidity and graft availability. Allografts and xenografts provide more accessible alternatives but are associated with higher risks of immune rejection and slower integration. In contrast, synthetic materials like titanium, PEEK (polyether ether ketone), and hydroxyapatite provide excellent mechanical strength and durability but often lack osteoinductive properties, requiring surface modifications to improve tissue integration.This review aims to provide a comprehensive analysis of the current materials used in mandibular reconstruction, comparing their biocompatibility, mechanical properties, osteoinductive potential, and clinical outcomes. Additionally, the review explores the growing role of composite materials that combine the strength of synthetics with the biological activity of natural tissues, as well as the advent of tissue engineering approaches that incorporate stem cell therapies and biomaterial scaffolds to promote bone regeneration. Emerging technologies such as 3D printing of custom-made implants and the application of nanotechnology for enhanced integration and infection control are also discussed as promising directions for future clinical applications. The findings highlight the need for continued research into optimizing biomaterial design and improving regenerative therapies to enhance patient-specific outcomes, reduce complications, and foster successful long-term integration of reconstructed mandibular structures. This review provides a roadmap for advancing both material science and clinical practice in the field of mandibular reconstruction.

118 Exploring the Association of Marital Status on Disease Stage at Presentation and Disease- Specific Outcomes in Cutaneous Head and Neck Melanoma Patients

118 Exploring the Association of Marital Status on Disease Stage at Presentation and Disease- Specific Outcomes in Cutaneous Head and Neck Melanoma Patients

Emergency centre thoracotomy for penetrating trauma: Insights from 2 South African district-level emergency centres.

Trauma is a major contributor to global disease burden, disproportionally affecting low- and middle-income countries, especially in the African Region. Emergency centre thoracotomy (ECT) is a potentially life-saving procedure for a sub-group of trauma patients in extremis. Most literature regarding ECT originated in high-income countries. This study aimed to describe patient, procedure and outcome characteristics of ECTs performed at two facilities in a resource-limited setting in South Africa. A retrospective chart review was performed at two district-level facilities in Cape Town from 1 April 2017 to 31 March 2021. All patients who underwent post-trauma thoracotomy in the emergency centre (EC) were eligible for inclusion. Cases were excluded if patients did not undergo thoracotomy in the EC, or if medical records were missing. Patients were identified using an electronic EC attendance register, and theatre records, which were screened using documented diagnoses and dispositions. Clinical notes were interrogated for information regarding patient demographics, mechanism of injury, clinical presentation, procedural characteristics (such as level of clinician, injury found, use of ultrasound). Outcomes measured were survival to specified endpoints, and neurological or functional outcomes. Over 4 years, 67 ECTs were performed (50 stabs, 17 gunshots). No ECTs were performed for blunt trauma. Most patients were male, with a median age of 25 years (IQR 21-33). More than two-thirds of patients presented with their own transport, and more than 80 % presented with signs of life. Most ECTs were performed by non-specialists. Survival to hospital discharge was 24 % (32 % for stabs, 0 % for gunshots). Neurological outcome was difficult to analyse, however seemed to be good in all but one survivor. The performance of ECT in this resource-limited district-level setting, followed by stabilisation and transfer of patients to tertiary hospitals seems to result in comparable or better survival rates than reported in international literature. Further research is needed to better describe the performance and outcomes of EC thoracotomies in a resource-limited setting. This study setting, with high incidence of trauma and ECT performed, provides an excellent opportunity for further research. Prospective studies may demonstrate correlations between specific patient and procedural characteristics and outcomes and may guide the development of local guidelines.

Evaluating safety and efficacy of plastic versus metal stenting in malignant hilar biliary obstruction: a systematic review and meta-analysis of randomized controlled trials.

Stenting malignant hilar biliary obstruction (MHBO) is challenging due to its complex structure, and it is less effective than blockages in the distal bile duct area. Plastic stents (PSs) and metal stents (MSs) are commonly used for stenting MHBO. This study aims to compare the outcomes of PSs and MSs in MHBO patients. We conducted a search of medical databases up to March 2024. Using a fixed-effect model, we analyzed the risk ratios (RRs) of the outcomes between the PS and MS groups. We calculated the RR for clinical and technical success, reinterventions, and adverse events, as well as the hazard ratio (HR) for survival and stent patency. This analysis includes five randomized controlled trials (RCTs) that met the inclusion criteria, comprising a total of 322 patients (156 in the PS group and 166 in the MS group). Significant differences (P < .05) in favor of the MS group were found in the reinterventions (RR 1.80, 95% CI 1.07-3.04), and stent patency (HR 0.54, 95% CI 0.32-0.90). There were no significant differences (P > 0.05) between the PS and MS groups regarding technical success (RR 1.01, 95% CI 0.94-1.09), clinical success (RR 0.86, 95% CI 0.69-1.07), overall survival (HR 0.71, 95% CI 0.47-1.05), stent migration (RR 0.69, 95% CI 0.08-6.02), stent occlusion (RR1.32, 95% CI 0.97-1.81), and adverse events (RR 0.80, 95% CI 0.53-1.20). Both PS and MS are effective for managing MHBO, while MS offers greater efficacy in increased stent patency and lower reintervention rates. Key message What is already known on this topic Metal stents (MSs) and plastic stents (PSs) are used for palliative treatment of malignant hilar biliary obstruction (MHBO). MSs significantly reduced the need for reinterventions compared to PSs in patients with MHBO. What this study adds There were no significant differences between MSs and PSs in terms of technical success, clinical success, overall survival, stent migration, stent occlusion, or adverse events. How this study might affect research, practice, or policy The study's findings may prompt researchers to design more targeted studies to further investigate these specific outcomes in MHBO patients. The results encourage endoscopists to consider patient-specific factors, such as life expectancy and preference for minimizing recurrent procedures, when choosing between MSs and PSs for MHBO.

Digital Smile Design Software: An Overview

Digital Smile Design (DSD) software have revolutionized the field of aesthetic dentistry by enabling clinicians to design and visualize patient-specific treatment outcomes. This software integrates digital tools like 2D and 3D imaging, CAD/CAM technology, and simulation algorithms to create comprehensive and highly accurate treatment plans. It facilitates communication between dentists, technicians, and patients by providing a visual representation of potential results, enhancing patient understanding and confidence. This article presents an overview of digital smile design software currently available.

Job Satisfaction and Associated Factors Among Public and Private Pharmacy Professionals in Gondar Town, Northwest Ethiopia.

The quality of the healthcare system and the achievement of specific patient outcomes rely on the contentment of pharmacy experts working in both public and private pharmacies. This study aims to evaluate and compare the levels of job satisfaction among pharmacy professionals employed in public and private medication retail outlets in Gondar town, northwest Ethiopia. A cross-sectional survey was conducted to assess job satisfaction and associated factors among pharmacy professionals in public and private pharmacies in Gondar town from July 20 to August 1, 2022. All pharmacy professionals were included in the study and no sample size was calculated. Bivariable and multivariable binary logistic regression analysis was used to identify the factors associated with job satisfaction and a p < 0.05 was considered significant with 95% CI. A total of 217 private and public pharmacy professionals were included in the study, and 183 volunteered to participate with a response rate of 84%. Among the study participants, 52.5% were dissatisfied with their job. The majority of the respondents (92.3%) believed that the job has a good future, 72% of them received good recognition from the community for their job and more than half (57.3%) received a good salary. Private pharmacy workers were found to be more satisfied than public pharmacy workers (AOR: 2.770), pharmacy professionals who had good salaries and benefits, (AOR: 0.302), and individuals who were closeness of their workplace to home (AOR: 0.298) were significantly associated with job satisfaction levels. In this study, more than half of participants were disatisfied with their job. Pharmacy professionals working in private medication retail outlets, who had good salaries and benefits, and lived close to their homes were significantly associated with job satisfaction levels.

What matters most to healthy older adults in treatment decision making: a discrete choice experiment

Abstract Introduction Shifting to a patient centered approach is crucial for a sustainable healthcare system. Understanding individuals’ priorities is essential for personalized care, especially in critical illness. Treatment decisions are often aimed at disease-specific outcomes such as life extension or survival, while patient-specific outcomes like maintaining independence may be equally vital. How healthy older adults prioritize treatment outcomes in case of a critical illness is currently unknown. Enhanced insight into their priorities can refine healthcare policy, for more personalized care. This study investigated outcomes (attributes) prioritized in hypothetical decision-making by healthy adults over 50 yr. Methods We conducted a Discrete Choice Experiment with individuals aged ≥50, comparing six pairs of hypothetical treatments with five attributes: life expectancy, independence, pain, memory complaints and societal costs. Attribute utility was analyzed using a conditional logit model, and latent class analyses were employed to explore preferences in groups. Results In 333 participants (mean age 70 +/- 7.7) all attributes emerged as impactful with independence being strongest (p &amp;lt; 0.05). Increased life expectancy had positive utility, but only for a two-year increase. Negative utility was found for all other attributes except mild pain and memory complaints. Latent class analyses identified two groups (22.4% and 77.6%). Group one valued life expectancy more (p .019 vs .940), whereas the second group valued independence (p .058 vs.&amp;lt;.001 and societal costs (p.053 vs. &amp;lt;.001) more. Conclusions In a hypothetical case of life-threatening disease, for people aged ≥ 50 life expectancy was not the sole relevant outcome for treatment decisions; pain, independence and societal costs are important and should be discussed in clinical decision making or healthcare policy. Key messages • Older adults find patient-specific outcomes relevant for decision making. • Societal costs are found relevant for decision making for treatment by older adults.

6844 Comparison of Lactated Ringers and Normal Saline in the Treatment of Diabetic Ketoacidosis

Abstract Disclosure: J.N. Johnson: None. A.T. Drincic: None. K. Nein: None. E. Buddenhagen: None. K. Samson: None. T. Langenhan: None. Background: Current guidelines recommend normal saline (NS) for fluid resuscitation in the management of patients presenting with diabetic ketoacidosis (DKA). However, previous prospective studies have demonstrated improvement in patient specific outcomes, including time to DKA resolution, when balanced crystalloid fluids are used. We hypothesized that the use of LR compared to NS for volume management in DKA will shorten time to DKA resolution, reduce time to DKA associated protocol insulin infusion discontinuation, and result in lower post-intravenous fluid resuscitation chloride values. Methods: We conducted a single institution, retrospective cohort study of patients admitted with the diagnosis of DKA following our institution’s transition from NS to lactated ringers (LR) as the default resuscitative and maintenance fluid in our DKA management protocol. Adult patients admitted with DKA before and after the protocol change were identified. The primary outcome was time from DKA clinical presentation until DKA resolution. The secondary outcome was time to discontinuation of DKA protocol continuous insulin infusion. Results: Of 246 patients meeting inclusion criteria, 119 were stratified to the NS group (pre-protocol change) and 127 to the LR group (post-protocol change). T-test analysis revealed decreased time to DKA resolution in the LR group (mean 17.1 hours; SD 11.02) relative to the NS group (mean 20.6 hours; SD 12.22; p = .02). Duration of DKA protocol continuous intravenous insulin was shorter in the LR group (mean 16.0 hours; SD 8.72) compared to the NS group (mean 21.4 hours; SD 12.50; p = 0.0001). Conclusions: In this retrospective cohort study, protocolized DKA intravenous fluid management with LR resulted in shorter time to resolution of DKA and reduced duration of DKA protocol continuous insulin infusion. Presentation: 6/2/2024

Developing an Individualized Patient Decision Aid for Chronic Coronary Disease Based on the ISCHEMIA Trial: A Mixed-Methods Study

BACKGROUND: Pursuing initial invasive or conservative management of chronic coronary disease (CCD) is a preference-sensitive decision that should include shared decision-making. Communicating the benefits of either approach is challenging, as individual patients rarely achieve the population-averaged outcomes reported in clinical trials. Our objective was to develop a patient decision aid (PDA) with patient-specific estimates of outcomes for initial invasive versus conservative management of CCD, based on the ISCHEMIA trial (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches). METHODS: This was a multiphase mixed-methods study using focus groups of outpatients with CCD, caregivers, clinicians, and researchers. Focus groups were held in Kansas City, MO and New York City, NY between September 2021 and June 2022. Patients with CCD were included if they had a positive stress test within 1 year. Phase 1 focused on patient priorities for outcomes to guide treatment decisions. Phase 2 involved PDA development and refinement. Phase 3 involved further refinement and member checking. Key themes involving shared decision-making and treatment preferences were elicited from focus groups using a deductive approach to develop a PDA representing the outcomes most important to patients. RESULTS: Of 46 patient and caregiver participants, the mean age was 63.5 years, 53% were female, 61% were White, 24% were Black, and 9% were Hispanic. When deciding between treatments, participants valued shared decision-making but generally deferred decisions to clinicians. The outcomes most important to participants were survival and quality of life, followed by physical functioning and symptoms. To represent these outcomes, participants favored simple visualizations, such as a speedometer or health meter. When deciding between treatment options, participants preferred to use the PDA collaboratively with a clinician instead of as a stand-alone tool. CONCLUSIONS: Our novel, patient-centered approach to developing a PDA for CCD with patient-specific outcomes has the potential to rapidly translate clinical trial results to individual patients and support shared decision-making.

Computational haemodynamics for pulmonary valve replacement by means of a reduced fluid-structure interaction model.

Pulmonary valve replacement (PVR) consists of substituting a patient's original valve with a prosthetic one, primarily addressing pulmonary valve insufficiency, which is crucially relevant in Tetralogy of Fallot repairment. While extensive clinical and computational literature on aortic and mitral valve replacements is available, PVR's post-procedural haemodynamics in the pulmonary artery and the impact of prosthetic valve dynamics remain significantly understudied. Addressing this gap, we introduce a reduced Fluid-Structure Interaction (rFSI) model, applied for the first time to the pulmonary valve. This model couples a three-dimensional computational representation of pulmonary artery haemodynamics with a one-degree-of-freedom model to account for valve structural mechanics. Through this approach, we analyse patient-specific haemodynamics pre and post PVR. Patient-specific geometries, reconstructed from CT scans, are virtually equipped with a template valve geometry. Boundary conditions for the model are established using a lumped-parameter model, fine-tuned based on clinical patient data. Our model accurately reproduces patient-specific haemodynamic changes across different scenarios: pre-PVR, six months post-PVR, and a follow-up condition after a decade. It effectively demonstrates the impact of valve implantation on sustaining the diastolic pressure gradient across the valve. The numerical results indicate that our valve model is able to reproduce overall physiological and/or pathological conditions, as preliminary assessed on two different patients. This promising approach provides insights into post-PVR haemodynamics and prosthetic valve effects, shedding light on potential implications for patient-specific outcomes.

Chronic Venous Insufficiency Evaluation and Medical Management.

This review will focus on comprehensive evaluation of chronic venous insufficiency (CVI), nuances in diagnostic testing and advances in medical therapies to provide improvement in patient specific outcomes. Chronic venous insufficiency of the lower extremities represents an often underrecognized source of morbidity. Comprehensive evaluation focuses on personal and family history of deep vein thrombosis and varicose veins. Diagnostic testing is initially with a thorough duplex ultrasound, but advanced imaging with CT scan and MRV may be indicated in selected patients who might benefit from more invasive intervention. Compression therapy, wraps and garments, remains the mainstay of conservative therapy for patients with CVI. In addition, there is renewed interest in lifestyle and nutritional supplements, most commonly micronized purified flavanoid fraction (MPFF), in relieving symptoms and preventing morbidity. A holistic approach to patients with CVI provides the best opportunity for enduring improvement in quality of life.

Analysis of hepatic lentiviral vector transduction; implications for preclinical studies and clinical gene therapy protocols.

Lentiviral vector-transduced T-cells were approved by the FDA as gene therapy anti-cancer medications. Little is known about the host genetic variation effects on the safety and efficacy of the lentiviral vector gene delivery system. To narrow this knowledge-gap, we characterized hepatic gene delivery by lentiviral vectors across the Collaborative Cross (CC) mouse genetic reference population. For 24 weeks, we periodically measured hepatic luciferase expression from lentiviral vectors in 41 CC mouse strains. Hepatic and splenic vector copy numbers were determined. We report that CC mouse strains showed highly diverse outcomes following lentiviral gene delivery. For the first time, moderate correlation between mouse strain-specific sleeping patterns and transduction efficiency was observed. We associated two quantitative trait loci (QTLs) with intra-strain variations in transduction phenotypes, which mechanistically relates to the phenomenon of metastable epialleles. An additional QTL was associated with the kinetics of hepatic transgene expression. Genes comprised in the above QTLs are potential targets to personalize gene therapy protocols. Importantly, we identified two mouse strains that open new directions in characterizing continuous viral vector silencing and HIV latency. Our findings suggest that wide-range patient-specific outcomes of viral vector-based gene therapy should be expected. Thus, novel escalating dose-based clinical protocols should be considered.

Video-Based Performance Analysis in Pituitary Surgery—Part 1: Surgical Outcomes

Endoscopic pituitary adenoma surgery has a steep learning curve, with varying surgical techniques and outcomes across centers. In other surgeries, superior performance is linked with superior surgical outcomes. This study aimed to explore the prediction of patient-specific outcomes using surgical video analysis in pituitary surgery. Endoscopic pituitary adenoma surgery videos from a single center were annotated by experts for operative workflow (3 surgical phases and 15 surgical steps) and operative skill (using modified Objective Structured Assessment of Technical Skills [mOSATS]). Quantitative workflow metrics were calculated, including phase duration and step transitions. Poisson or logistic regression was used to assess the association of workflow metrics and mOSATS with common inpatient surgical outcomes. 100 videos from 100 patients were included. Nasal phase mean duration was 24minutes and mean mOSATS was 21.2/30. Mean duration was 34minutes and mean mOSATS was 20.9/30 for the sellar phase, and 11minutes and 21.7/30, respectively, for the closure phase. The most common adverse outcomes were new anterior pituitary hormone deficiency (n= 26), dysnatremia (n= 24), and cerebrospinal fluid leak (n= 5). Higher mOSATS for all 3 phases and shorter operation duration were associated with decreased length of stay (P= 0.003 &P < 0.001). Superior closure phase mOSATS were associated with reduced postoperative cerebrospinal fluid leak (P < 0.001), and superior sellar phase mOSATS were associated with reduced postoperative visual deterioration (P= 0.041). Superior surgical skill and shorter surgical time were associated with superior surgical outcomes, at a generic and phase-specific level. Such video-based analysis has promise for integration into data-driven training and service improvement initiatives.

Metabolic and Oxidative Stress Management Heterogeneity in a Panel of Breast Cancer Cell Lines.

Metabolic alterations are recognized as one of the hallmarks of cancer. Among these, alterations in mitochondrial function have been associated with an enhanced production of Reactive Oxygen Species (ROS), which activate ROS-regulated cancer cell signaling pathways. Breast cancer is the main cancer-related cause of death for women globally. It is a heterogeneous disease with subtypes characterized by specific molecular features and patient outcomes. With the purpose of identifying differences in energy metabolism and the oxidative stress management system in non-tumorigenic, estrogen receptor positive (ER+) and triple negative (TN) breast cancer cells, we evaluated ROS production, protein enzyme levels and activities and profiled energy metabolism. We found differences in energetic metabolism and ROS management systems between non-tumorigenic and cancer cells and between ER+ and TN breast cancer cells. Our results indicate a dependence on glycolysis despite different glycolytic ATP levels in all cancer cell lines tested. In addition, our data show that high levels of ROS in TN cells are a result of limited antioxidant capacity in the NADPH producing and GSH systems, mitochondrial dysfunction and non-mitochondrial ROS production, making them more sensitive to GSH synthesis inhibitors. Our data suggest that metabolic and antioxidant profiling of breast cancer will provide important targets for metabolic inhibitors or antioxidant treatments for breast cancer therapy.